Allergic to Dogs and Allergies in Dogs Resource

Eicosanoid Inflammatory Mediators (Leukotrienes and Prostaglandins) and Allergies

What are Eicosanoids?

Eicosanoids (a.k.a. icosanoids) are autocrine (influence or regulate cells that produce them) and paracrine (influence or regulate cells in close vicinity) chemical mediators that are synthesized on demand and not stored in cells. They are rapidly deactivated into inactive metabolites within seconds or minutes before entering the circulation.

Eicosanoids classification varies between authorities but one possible method is as follows:

Classical Eicosanoids Leukotrienes
Prostanoids (prostaglandins, prostacyclins and thromboxanes)
Non-Classical Eicosanoids Endocannabinoid
Epoxyeicosatrienoic acids
Epi-lipoxins Hepoxilins


Sequence of Events Involved in Eicosanoid Biosynthesis

Note: Enzymes involved are highlighted in green


Cell activated
By various stimuli, cytokines or mechanical trauma

Cell membrane
Phospholipase (enzyme) released which enters nuclear membrane

Nuclear Membrane
Phospholipase react with either
phospholipid (phospholipase A2 ) or diacylglycerol (phospholipase C)

Essential Fatty Acid released
The 2 families of essential fatty acid include

Omega 3 family

Various enzyme reactions result in production of the eicosanoid precursor:

  • Eicosapentaenoic acid (EPA)

Omega 6 family

Various enzyme reactions result in production of the eicosanoid precursors:

  • Dihomo-gamma-linolenic acid (DLGA) from  γ-Linolenic acid (GLA)
  • Arachidonic acid (AA)

Eicosanoids Influence on Inflammatory Response

Inflammatory response is then determined by the type of eicosanoids that are formed as a result of 3 parallel and competing cascades:

  • AA cascade is the main form in humans and produces many pro-inflammatory eicosanoids.
  • EPA cascade is more prominant than the DLGA cascade but both of these produce less-inflammatory, inactive or anti-inflammatory eicosanoids. 
  • The competition of the EPA/DLGA cascades with the AA cascade helps determine the intensity of the inflammatory response.



Eicosanoids, Arachidonic Acid and Allergies

Arachidonic acid can be metabolized by 3 possible pathways:

Cyclooxygenase pathway

Lipoxygenase pathway

Epoxygenase pathway

(COX-1)    or
Lipoxygenases Epoxidase 
Different Prostanoids are formed by various  enzyme reactions and these include:

  • Prostaglandins:
    PGD2, PGE2, PGF2α,
  • Prostacyclins:
  • Thromboxane:
  • Note: 2 denotes series-2
Different leukotrienes  are formed by various  enzyme reactions including:

  • LTA4, LTB4, LTC4, LTD4, LTE4
  • Note: 4 denotes series-4
Epoxytrienoic acids (EETs) formed are antihypertensives

EPA CASCADE results in:

  • Prostaglandins:
    PGD3, PGE3, PGF3α,
  • Prostacyclins:
  • Thromboxane:
  • Note: 3 denotes series-3

  • LTA5, LTB5, LTC5, LTD5
  •  Note: 5 denotes series-5

DGLA CASCADE results in:

  • Prostaglandins:
    PGE1, PG1α
  • Thromboxane:
  • Note: 1 denotes series-1
Blocks Leukotriene 4 formation
e.g. 15-HETrE metabolized from DGLA inhibits 5-LOX enzyme involved in the production of  the potent inflammatory leukotriene LTB4
Note: 4 denotes series-4


Eicosanoids, Inflammation and Dietary Levels of Omega-3 and Omega-6

Eicosanoids are derived from the essential fatty acids omega-3 and omega-6 and play a notable role in inflammation, immunity and as central nervous system messengers. 

Eicosanoids derived from arachidonic acid (omega-6 family) are considered to be generally pro-inflammatory, whereas those from DGLA (also omega-6 family) or the omega-3 EPA, are typically less inflammatory, inactive or anti-inflammatory in nature.

Although both omega-3 and 6 are essential for good health, some scientists consider the disproportionate consumption of omega-6 rich foods observed in the Western diet (omega-3 and omega-6 balance) as a major contributor to various diseases including cardiovascular disease and inflammatory conditions such as arthritis. However, others believe that the importance of omega-6 is overshadowed by the significant beneficial impact made by having a diet rich in omega-3.

A diet rich in omega-3 may be beneficial because:

  • Less arachidonic acid (from omega-6 family)  is available to produce pro-inflammatory omega-6 eicosanoids
  • Any arachidonic acid present has to compete with higher levels of EPA (from omega-3 family) and as well as any DGLA, for access to the enzymes (cyclooxygenase and lipoxygenase) it requires to produce pro-inflammatory omega-6 eicosanoids.
  • The pro-inflammatory omega-6 eicosanoids derived from arachidonic acid are counteracted by those derived from omega-3 EPA as well as those from DGLA.

What are Leukotrienes?

When the body is exposed to allergens, histamine and other inflammatory chemical mediators are produced. Leukotrienes play a significant role in inflammation because these inflammatory chemicals are three to four orders of magnitude (1,000-10,000) more potent and longer lasting than histamine (Hammarström 1983, Schmidt and Rabe 2000)

Leukotrienes are produced in white blood cells/leukocytes and other immune cells (mast cells), and similar to prostaglandins, they are synthesized from arachidonic acid (Hallstrand and Henderson 2010). Different enzymes determine whether prostaglandins (Cyclooxygenase/cyclooxygenase pathway) or leukotrienes (Lipoxygenases/lipoxygenase pathway) are produced (See above: Sequence of Events Involved in Eicosanoid Biosynthesis).

There are two families of leukotrienes  (Berger 1999) and these are primarily associated with:

  • Conditions where inflammation is dependent on neutrophils e.g. cystic fibrosis, psoriasis.
  • Cysteinyl leukotrienes: Bronchoconstriction in asthma induced by eosinophils and mast cells and they play a role in anaphylaxis.

Leukotrienes cause tightening (bronchoconstriction) and inflammation of the airways as well as the production of excessive mucus. They also increase vascular permeability (Dahlén et al 1981) and recruit white blood cell to areas of inflammation. Leukotrienes appear to be associated with various diseases involving inflammatory or immediate hypersensitivity reactions including allergy responses, allergic rhinitis, nasal allergies and autoallergenic diseases e.g. asthma, inflammatory bowel disease, lupus, psoriasis and rheumatoid arthritis. Furthermore, they may play a role in atherosclerosis, heart attacks, strokes and some types of cancer.

Medicines used to decrease the production and block the action of leukotrienes are called leukotriene antagonists or modifiers, and these can reduce allergy symptoms, airway inflammatory damage as well as play a role in preventing asthma. However, they are not suitable for treating an actual asthma attack.

From a natural allergy treatment perspective, the anti-inflammatory nature of the plant pigment Quercetin may help allergy sufferers through lowering leukotriene formation by blocking the enzymes lipoxygenase and phospholipase A2 that are involved in the lipoxygenase pathway.

What are Prostaglandins?

Prostaglandins are derived from essential fatty acids, namely omega-3 (EPA) and omega-6 (GLA via DGLA, and arachidonic acid) and are produced in all body cells except red blood cells. They are made ‘onsite’ and localized where and when required; although hormone-like, this contrasts with typical endocrine hormones that are produced in one location then transported in the bloodstream to work at some distant site. Prostaglandins are broken down by the body quickly which helps localize and control the impact they can have.

Prostaglandins are associated with tissue damage or infection and thereby injury and illness. As part of the healing process they promote tissue inflammation, fever and pain. The relationship between body condition and prostaglandin levels relates to prostaglandin synthesis from arachidonic acid and its dependency on the enzyme cyclooxygenase as shown below:

Normal Cyclooxygenase 1 (COX-1) Normal
Elevated Cyclooxygenase 2 (COX-2) Injury or Inflammation

 Note: 3 versions of cyclooxygenase are currently known, although COX-3 function is at present unclear.

The interplay between different types of prostaglandins and the various receptors (10 currently known) they interact with throughout the body determines the resulting actions. Even though it may appear the various prostaglandins sometimes counteract each other, when viewed collectively, they play an important role in regulating and protecting the body by influencing every organ system e.g. blood vessel constriction and dilation (blood flow), electrolytes, lipolysis, muscle contraction, permeability.

Furthermore, prostaglandins are involved in the following:

  • Female reproduction/ovulation and stimulating sperm formation and testosterone secretion.
  • Lowering stomach acid production and blood pressure.
  • Promoting blood clotting, cardiac circulation and nerve function, cortisol production, gastrointestinal mucus secretions, sodium retention and T-cells.

The pharmaceutical manipulation of prostaglandins can be used to medical advantage, although doing so involves a trade-off between benefits and side-effects. For example:

  • When natural prostaglandin levels are too high, controlling them pharmaceutically can help tackle unwanted inflammation associated with various conditions e.g. arthritis or certain cancers. The interplay between non-steroidal anti-inflammatory (NSAIDs) medications and prostaglandins is noteworthy because it provides a glimpse of the dynamic interplay and impact prostaglandins have on the body. Classical NSAIDs (as opposed to newer NSAIDs that selectively inhibit COX-2), such as Aspirin or Ibuprofen, block all types of cyclooxygenase (COX) enzymes which reduces prostaglandin levels with the following outcome:
POSITIVE EFFECTS Provide relief of inflammation (anti-inflammatory), pain (analgesic) and fever (antipyretic) Prostaglandins promote pain and fever
Prevent blood clots (antithrombotic) associated with heart disease Prostaglandins promote blood clotting
NEGATIVE EFFECTS Stomach/gastrointestinal upset Prostaglandins inhibit stomach acid production and promote mucus production
Possible intestinal bleeding Prostaglandin  promotes blood clotting


Conversely, increasing prostaglandin levels pharmaceutically may also prove beneficial in some situations e.g. treating stomach ulcers or inducing labor.

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